Intro: An FDA re-analysis of pediatric clinical trials (N about 4400) in psychiatric conditions found that the risk of suicidal ideation and behavior (suicidality) was significantly higher with antidepressants (4%) compared to placebo (2%). These data revealed that the suicidality signal was not limited to depression: subjects with OCD and other anxiety disorders also exhibited this higher risk. Although the mechanism responsible for this effect is unknown, induction of an "activation syndrome" (e.g., irritability, restlessness, emotional lability, etc.) may represent an intermediary state change that promotes suicidality. SSRI-induced activation syndrome is well-accepted by clinicians and thought to be common, particularly in children and teens. However, there is a dearth of empirical data on the phenomenology and quantification of this putative syndrome. We conceptualize activation syndrome as behavioral toxicity (an adverse event) that occurs relatively independent of the underlying diagnosis, while acknowledging that various factors may modify susceptibility and expression (e.g., age, dosing, pharmacogenetics, comorbidity, etc.). Better characterization of activation syndrome and its timing might point to the mechanisms mediating this adverse effect as well as approaches to its mitigation. Specific Aims are: 1. To formalize and quantify a cluster of behavioral side effects of SSRIs, referred to as "activation syndrome" and 2. To confirm the occurrence and timing of activation syndrome during SSRI treatment. Approach: The first phase will entail an iterative process of arriving at consensus on the content domains corresponding to activation syndrome, selection and revision of measures, creation of a composite measure and testing of reliability in a representative sample of children and adolescents at various stages of treatment with SSRIs. In the second phase, children and adolescents with OCD will be randomized in double-blind fashion to either 1) sertraline at standard dosing (RegSert); 2) sertraline slow titration (SloSert); or 3) pill placebo (Pla) for 18 weeks. All groups will receive CBT for their OC symptoms starting after week 4. We predict that measures of activation syndrome will be elevated early (first days or 2 weeks) during RegSert compared to PLA. We will explore if SloSert reduces frequency or intensity of activation syndrome compared to RegSert. Conducting this study in OCD offers pragmatic advantages (e.g., clarity of diagnosis), yet findings should be generalizable to other diagnostic groups. Significance: SSRIs induce an activation syndrome (consisting of irritability, agitation, mood swings, etc.) that may be a precursor to suicidality in some individuals. Improved recognition and understanding of activation syndrome should prompt interventions (e.g., slower dosing of antidepressants) that might reduce the risk of developing suicidality. Development of an activation syndrome measurement tool will be useful in future large-scale clinical trials that test the relationship between activation syndrome and suicidality. [unreadable] [unreadable] [unreadable]